Macrophage colony‐stimulating factor potentially induces recruitment and maturation of macrophages in recurrent pituitary neuroendocrine tumors
Macrophage colony‐stimulating factor potentially induces recruitment and maturation of macrophages in recurrent pituitary neuroendocrine tumors
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DOI：
10.1111/1348-0421.13041
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发表时间：
2022-12
影响因子：
2.6
通讯作者：
Hiroaki Matsuzaki;Y. Komohara;H. Yano;Yukio Fujiwara;Keitaro Kai;Rin Yamada;D. Yoshii;Ken Uekawa;N. Shinojima;Yoshiki Mikami;A. Mukasa
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文献类型：
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作者：
Hiroaki Matsuzaki;Y. Komohara;H. Yano;Yukio Fujiwara;Keitaro Kai;Rin Yamada;D. Yoshii;Ken Uekawa;N. Shinojima;Yoshiki Mikami;A. Mukasa
虽然垂体神经内分泌肿瘤（PitNETs）通常是良性的，但有些是高度侵袭性和复发性的。复发性PitNET通常具有治疗抗性，目前尚无有效的循证治疗。肿瘤相关巨噬细胞（TAM）在许多癌症中促进肿瘤生长，但TAM对PitNET的影响仍不清楚。本研究调查了TAM在复发性PitNET发生率中的作用。免疫组化分析显示，CD 163和CD 204阳性TAM的密度在复发性PitNET中倾向于增加。与原发灶的TAM相比，复发灶的TAM增大。为了阐明TAM和PitNET之间的细胞-细胞相互作用，使用小鼠PitNET细胞系AtT 20和小鼠巨噬细胞系J774进行体外实验。与巨噬细胞趋化性和分化相关的几种细胞因子，如M-CSF，通过巨噬细胞条件培养基刺激显著升高。当使用人PitNET样本进行M-CSF免疫组织化学分析时，与原发性病变相比，复发性病变中的M-CSF表达显著增加。虽然在原发性和复发性PitNET的肿瘤细胞中未观察到M-CSF受体（M-CSFR）表达，但流式细胞术分析显示小鼠PitNET细胞系表达M-CSFR。小鼠PitNET中的细胞增殖被高浓度的M-CSFR抑制剂抑制，表明PitNET和巨噬细胞之间的细胞间通讯诱导M-CSF表达，这反过来增强了肿瘤微环境中的TAM趋化性和成熟。阻断M-CSFR信号通路可能是治疗复发性PitNET的一种新的治疗辅助手段。
Although pituitary neuroendocrine tumors (PitNETs) are usually benign, some are highly invasive and recurrent. Recurrent PitNETs are often treatment‐resistant and there is currently no effective evidence‐based treatment. Tumor‐associated macrophages (TAMs) promote tumor growth in many cancers, but the effect of TAMs on PitNETs remains unclear. This study investigated the role of TAMs in the incidence of recurrent PitNETs. Immunohistochemical analysis revealed that the densities of CD163‐ and CD204‐positive TAMs tended to increase in recurrent PitNETs. Compared with TAMs in primary lesions, those in recurrent lesions were enlarged. To clarify the cell–cell interactions between TAMs and PitNETs, in vitro experiments were performed using a mouse PitNET cell line AtT20 and the mouse macrophage cell line J774. Several cytokines related to macrophage chemotaxis and differentiation, such as M‐CSF, were elevated significantly by stimulation with macrophage conditioned medium. When M‐CSF immunohistochemistry analysis was performed using human PitNET samples, M‐CSF expression increased significantly in recurrent lesions compared with primary lesions. Although no M‐CSF receptor (M‐CSFR) expression was observed in tumor cells of primary and recurrent PitNETs, flow cytometric analysis revealed that the mouse PitNET cell line expressed M‐CSFR. Cellular proliferation in mouse PitNETs was inhibited by high concentrations of M‐CSFR inhibitors, suggesting that cell‐to‐cell communication between PitNETs and macrophages induces M‐CSF expression, which in turn enhances TAM chemotaxis and maturation in the tumor microenvironment. Blocking the M‐CSFR signaling pathway might be a novel therapeutic adjuvant in treating recurrent PitNETs.